The broad, long term objectives of this research are to use NMR and quantum chemical methods to learn more about protein structure and function and to apply these methods to protein structure prediction and refinement, including the topic of enzyme/inhibitor or drug/target interactions. The first specific aim is to compute NMR shielding surfaces for side-chains in amino acids; to calibrate these theoretical results versus experimental shielding tensors and orientations, and to incorporate these results into a Web Chemical Shift calculator, as well as the CNS program, for use in protein and peptide structure determination. Second, we will use combined multinuclear (1-H, 2-H, 17-O) NMR and quantum chemical methods to investigate hydrogen bonding and electrostatics in peptides and proteins. Third, we will use NMR, x-ray diffraction and quantum chemical methods to probe enzyme-inhibitor interactions, focussing on the bisphosphonate class of drugs which inhibit the enzymes farnesyl pyrophosphate and geranylgeranyl pyrophosphate synthase, and which have potent bone anti-resorptive, anti-cancer and anti-parasitic activity. The fourth and final specific aim is to use NMR and quantum chemical methods to develop improved approaches for quantitative structure-activity relationship studies (quantum QSAR applications).